RADX promotes genome stability and modulates chemosensitivity by regulating RAD51 at replication forks
| Autor: | Sarah R. Wessel, Aditya A. Sathe, David Cortez, Runxiang Zhao, Shyam K. Sharan, Huzefa Dungrawala, Xia Ding, Remy Le Meur, Kamakoti P. Bhat, Walter J. Chazin |
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| Přispěvatelé: | National Cancer Institute Frederick, Department of Biochemistry, Vanderbilt University School of Medicine [Nashville] |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Replication fork reversal Genome instability Models Molecular DNA Repair RAD51 Replication Origin [SDV.BC]Life Sciences [q-bio]/Cellular Biology Biology Poly(ADP-ribose) Polymerase Inhibitors medicine.disease_cause Transfection DNA-binding protein Article Genomic Instability Replication fork protection 03 medical and health sciences Mice Neoplasms medicine Animals Humans [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology DNA Breaks Double-Stranded Molecular Biology ComputingMilieux_MISCELLANEOUS BRCA2 Protein Dose-Response Relationship Drug Cell Biology DNA Neoplasm Molecular biology Cell biology Gene Expression Regulation Neoplastic enzymes and coenzymes (carbohydrates) 030104 developmental biology HEK293 Cells A549 Cells Drug Resistance Neoplasm Cancer cell PARP inhibitor Mutation RNA Interference Rad51 Recombinase biological phenomena cell phenomena and immunity CRISPR-Cas Systems Carcinogenesis Protein Binding |
| Zdroj: | Molecular Cell Molecular Cell, Elsevier, 2017, 67 (3), pp.374-386.e5. ⟨10.1016/j.molcel.2017.06.023⟩ |
| ISSN: | 1097-2765 |
| DOI: | 10.1016/j.molcel.2017.06.023⟩ |
| Popis: | RAD51 promotes homology-directed repair (HDR), replication fork reversal, and stalled fork protection. Defects in these functions cause genomic instability and tumorigenesis but also generate hypersensitivity to cancer therapeutics. Here we describe the identification of RADX as an RPA-like, single-strand DNA binding protein. RADX is recruited to replication forks, where it prevents fork collapse by regulating RAD51. When RADX is inactivated, excessive RAD51 activity slows replication elongation and causes double-strand breaks. In cancer cells lacking BRCA2, RADX deletion restores fork protection without restoring HDR. Furthermore, RADX inactivation confers chemotherapy and PARP inhibitor resistance to cancer cells with reduced BRCA2/RAD51 pathway function. By antagonizing RAD51 at forks, RADX allows cells to maintain a high capacity for HDR while ensuring that replication functions of RAD51 are properly regulated. Thus, RADX is essential to achieve the proper balance of RAD51 activity to maintain genome stability. |
| Databáze: | OpenAIRE |
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